Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC₅₀ = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC₅₀ = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.